The objectives of the Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (TSGVC) consortium are to thoroughly investigate and identify susceptibility loci for colorectal cancer, to characterize the biologic basis of inherited susceptibility, and to recognize how genetic variation may be quantified and modified by genetic and environmental risk factors. This long-term goal will be achieved through an integrated design with three highly-related Areas of investigation and an Administrative Core. Within Area 1, the program proposes a combined analysis of five existing genome-wide association studies (GWAS) with approximately 7,000 cases and 7,000 controls, followed by an accelerated, integrated approach to characterize new susceptibility loci in two replication phases. In the first replication phase, 8,000 cases will be genotyped and compared to publicly available data on ~8,000 controls from the Welcome Trust Case Control Consortium. A second replication phase evaluates candidate SNPs in more than 9,000 cases and 9,000 controls to confirm new susceptibility loci, gene by gene interactions, gene by environment interactions, and pathway-based analyses. Within Area 2, the program will establish a comprehensive strategy to study the biological implications of the diverse and robustly replicated associations identified through GWA studies of colorectal cancer, Area 3 develops a framework for understanding how replicated associations are modified by known epidemiologic risk factors for colorectal cancer, estimates the penetrance and population attributable risk of variants, and develops complex risk models that incorporate genetic and environmental risk factors. An Administrative Core coordinates the research and bioinformatic efforts of the investigative team, interacts with other trans-initiative investigators, and facilitates joint activities between NCI and the consortium.